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Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 66108

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Dr. Apirat Chaikuad

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Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany
Interests: structural biology; protein crystallography; structure-based inhibitor development; chemical biology of signaling pathway; protein kinases

Special Issue Information

Dear Colleagues,

Biologically active small molecules that can modulate protein functions provide a powerful tool in the exploration of biology. During the past decades, advances in structural biology methodologies have accelerated the development of chemical modulators by not only assisting chemistry design but offering insights into their modes of action. Many compounds capable of inducing phenotypic changes at the cellular or even organism levels have expanded the repertoire of biological processes and in some cases opened new chemotherapeutic opportunities for disease treatment. Despite many successes, our understanding of human diseases remains limited in many instances. Unlocking the ‘untargeted’ proteome to expand the proteomic space has been tabled as a new global challenge under the ‘Target 2035’ program. Therefore, we have launched the Special Issue “Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond” of the International Journal of Molecular Sciences for research papers and reviews about structure-based inhibitor development and chemical biology, which elucidate functions as well as potential modulations of the untargeted proteins at molecular levels. In addition, studies on early inhibitor designs, methodologies for unlocking the undruggable proteome, and potential alternative functions of proteins with existing chemical modulators will be considered.

Dr. Apirat Chaikuad
Guest Editor

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Keywords

structure-based inhibitor design
chemical biology
untargeted proteins
undruggable proteome
chemical probe
chemical modulators
target 2035
small molecule screening
inhibitor discovery
protein structures

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Published Papers (12 papers)

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Research

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17 pages, 11393 KiB

Open AccessArticle

Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP)

by Lester J Lambert, Stefan Grotegut, Maria Celeridad, Palak Gosalia, Laurent JS De Backer, Andrey A Bobkov, Sumeet Salaniwal, Thomas DY Chung, Fu-Yue Zeng, Ian Pass, Paul J Lombroso, Nicholas DP Cosford and Lutz Tautz

Int. J. Mol. Sci. 2021, 22(9), 4417; https://doi.org/10.3390/ijms22094417 - 23 Apr 2021

Cited by 9 | Viewed by 4445

Abstract

Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as “undruggable” and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer’s disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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18 pages, 3739 KiB

Open AccessArticle

The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification

by Carrow I. Wells, Hassan Al-Ali, David M. Andrews, Christopher R. M. Asquith, Alison D. Axtman, Ivan Dikic, Daniel Ebner, Peter Ettmayer, Christian Fischer, Mathias Frederiksen, Robert E. Futrell, Nathanael S. Gray, Stephanie B. Hatch, Stefan Knapp, Ulrich Lücking, Michael Michaelides, Caitlin E. Mills, Susanne Müller, Dafydd Owen, Alfredo Picado, Kumar S. Saikatendu, Martin Schröder, Alexandra Stolz, Mariana Tellechea, Brandon J. Turunen, Santiago Vilar, Jinhua Wang, William J. Zuercher, Timothy M. Willson and David H. Drewry Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(2), 566; https://doi.org/10.3390/ijms22020566 - 8 Jan 2021

Cited by 59 | Viewed by 8789

Abstract

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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37 pages, 6894 KiB

Open AccessArticle

Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK

by Michael Forster, Xiaojun Julia Liang, Martin Schröder, Stefan Gerstenecker, Apirat Chaikuad, Stefan Knapp, Stefan Laufer and Matthias Gehringer

Int. J. Mol. Sci. 2020, 21(23), 9269; https://doi.org/10.3390/ijms21239269 - 4 Dec 2020

Cited by 20 | Viewed by 4971

Abstract

The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton’s tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC₅₀ values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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13 pages, 4910 KiB

Open AccessArticle

Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms

by Apirat Chaikuad, Julius Pollinger, Michael Rühl, Xiaomin Ni, Whitney Kilu, Jan Heering and Daniel Merk

Int. J. Mol. Sci. 2020, 21(22), 8457; https://doi.org/10.3390/ijms21228457 - 11 Nov 2020

Cited by 18 | Viewed by 3720

Abstract

The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the saturated fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also observed an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concentrations of these highly abundant lipids, our results suggest their potential involvement in RXR signaling. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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18 pages, 3727 KiB

Open AccessArticle

Chemical Space Exploration of Oxetanes

by Fernando Rodrigues de Sá Alves, Rafael M. Couñago and Stefan Laufer

Int. J. Mol. Sci. 2020, 21(21), 8199; https://doi.org/10.3390/ijms21218199 - 2 Nov 2020

Cited by 4 | Viewed by 4285

Abstract

This paper focuses on new derivatives bearing an oxetane group to extend accessible chemical space for further identification of kinase inhibitors. The ability to modulate kinase activity represents an important therapeutic strategy for the treatment of human illnesses. Known as a nonclassical isoster of the carbonyl group, due to its high polarity and great ability to function as an acceptor of hydrogen bond, oxetane seems to be an attractive and underexplored structural motif in medicinal chemistry. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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14 pages, 3033 KiB

Open AccessArticle

Crystal Structure and Inhibitor Identifications Reveal Targeting Opportunity for the Atypical MAPK Kinase ERK3

by Martin Schröder, Panagis Filippakopoulos, Martin P. Schwalm, Carla A. Ferrer, David H. Drewry, Stefan Knapp and Apirat Chaikuad

Int. J. Mol. Sci. 2020, 21(21), 7953; https://doi.org/10.3390/ijms21217953 - 26 Oct 2020

Cited by 6 | Viewed by 4668

Abstract

Extracellular signal-regulated kinase 3 (ERK3), known also as mitogen-activated protein kinase 6 (MAPK6), is an atypical member of MAPK kinase family, which has been poorly studied. Little is known regarding its function in biological processes, yet this atypical kinase has been suggested to play important roles in the migration and invasiveness of certain cancers. The lack of tools, such as a selective inhibitor, hampers the study of ERK3 biology. Here, we report the crystal structure of the kinase domain of this atypical MAPK kinase, providing molecular insights into its distinct ATP binding pocket compared to the classical MAPK ERK2, explaining differences in their inhibitor binding properties. Medium-scale small molecule screening identified a number of inhibitors, several of which unexpectedly exhibited remarkably high inhibitory potencies. The crystal structure of CLK1 in complex with CAF052, one of the most potent inhibitors identified for ERK3, revealed typical type-I binding mode of the inhibitor, which by structural comparison could likely be maintained in ERK3. Together with the presented structural insights, these diverse chemical scaffolds displaying both reversible and irreversible modes of action, will serve as a starting point for the development of selective inhibitors for ERK3, which will be beneficial for elucidating the important functions of this understudied kinase. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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11 pages, 4030 KiB

Open AccessCommunication

Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics

by Isabelle Meijer, Sabine Willems, Xiaomin Ni, Jan Heering, Apirat Chaikuad and Daniel Merk

Int. J. Mol. Sci. 2020, 21(21), 7895; https://doi.org/10.3390/ijms21217895 - 24 Oct 2020

Cited by 16 | Viewed by 3459

Abstract

Hepatocyte nuclear factor 4α (HNF4α) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4α gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure–activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4α activity in a low micromolar range. These compounds demonstrate the druggability of HNF4α and thus provide a starting point for medicinal chemistry as well as an early tool for chemogenomics. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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41 pages, 3505 KiB

Open AccessArticle

Discovery and Evaluation of Enantiopure 9H-pyrimido[4,5-b]indoles as Nanomolar GSK-3β Inhibitors with Improved Metabolic Stability

by Stanislav Andreev, Tatu Pantsar, Ahmed El-Gokha, Francesco Ansideri, Mark Kudolo, Débora Bublitz Anton, Giulia Sita, Jenny Romasco, Christian Geibel, Michael Lämmerhofer, Márcia Ines Goettert, Andrea Tarozzi, Stefan A. Laufer and Pierre Koch

Int. J. Mol. Sci. 2020, 21(21), 7823; https://doi.org/10.3390/ijms21217823 - 22 Oct 2020

Cited by 6 | Viewed by 3838

Abstract

Glycogen synthase kinase-3β (GSK-3β) is a potential target in the field of Alzheimer’s disease drug discovery. We recently reported a new class of 9H-pyrimido[4,5-b]indole-based GSK-3β inhibitors, of which 3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide-based derivatives and studied their structure–activity relationships against GSK-3β supported by 1 µs molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)-3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC₅₀ values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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14 pages, 2513 KiB

Open AccessArticle

Functional Expression of Adenosine A₃ Receptor in Yeast Utilizing a Chimera with the A_2AR C-Terminus

by Abhinav R. Jain and Anne S. Robinson

Int. J. Mol. Sci. 2020, 21(12), 4547; https://doi.org/10.3390/ijms21124547 - 26 Jun 2020

Cited by 4 | Viewed by 4527

Abstract

The adenosine A₃ receptor (A₃R) is the only adenosine receptor subtype to be overexpressed in inflammatory and cancer cells and therefore is considered a novel and promising therapeutic target for inflammatory diseases and cancer. Heterologous expression of A₃R at levels to allow biophysical characterization is a major bottleneck in structure-guided drug discovery efforts. Here, we apply protein engineering using chimeric receptors to improve expression and activity in yeast. Previously we had reported improved expression and trafficking of the chimeric A₁R variant using a similar approach. In this report, we constructed chimeric A₃/A_2AR comprising the N-terminus and transmembrane domains from A₃R (residues 1–284) and the cytoplasmic C-terminus of the A_2AR (residues 291–412). The chimeric receptor showed approximately 2-fold improved expression with a 2-fold decreased unfolded protein response when compared to wild type A₃R. Moreover, by varying culture conditions such as initial cell density and induction temperature a further 1.7-fold increase in total receptor yields was obtained. We observed native-like coupling of the chimeric receptor to G_ai-Gpa1 in engineered yeast strains, activating the downstream, modified MAPK pathway. This strategy of utilizing chimeric receptor variants in yeast thus provides an exciting opportunity to improve expression and activity of “difficult-to-express” receptors, expanding the opportunity for utilizing yeast in drug discovery. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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Review

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25 pages, 4943 KiB

Open AccessReview

Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

by Yuxiang Luo and Huilin Li

Int. J. Mol. Sci. 2020, 21(22), 8828; https://doi.org/10.3390/ijms21228828 - 22 Nov 2020

Cited by 38 | Viewed by 7403

Abstract

Class I histone deacetylases (HDACs) are promising targets for epigenetic therapies for a range of diseases such as cancers, inflammations, infections and neurological diseases. Although six HDAC inhibitors are now licensed for clinical treatments, they are all pan-inhibitors with little or no HDAC isoform selectivity, exhibiting undesirable side effects. A major issue with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Except for HDAC8, Class I HDACs (1, 2 and 3) are recruited to large multiprotein complexes to function. Therefore, there are rising needs to develop new, hopefully, therapeutically efficacious HDAC inhibitors with isoform or complex selectivity. Here, upon the introduction of the structures of Class I HDACs and their complexes, we provide an up-to-date overview of the structure-based discovery of Class I HDAC inhibitors, including pan-, isoform-selective and complex-specific inhibitors, aiming to provide an insight into the discovery of additional HDAC inhibitors with greater selectivity, specificity and therapeutic utility. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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31 pages, 7741 KiB

Open AccessReview

Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

by Paula Martín Moyano, Václav Němec and Kamil Paruch

Int. J. Mol. Sci. 2020, 21(20), 7549; https://doi.org/10.3390/ijms21207549 - 13 Oct 2020

Cited by 51 | Viewed by 8709

Abstract

Protein kinases represent a very pharmacologically attractive class of targets; however, some members of the family still remain rather unexplored. The biology and therapeutic potential of cdc-like kinases (CLKs) have been explored mainly over the last decade and the first CLK inhibitor, compound SM08502, entered clinical trials only recently. This review summarizes the biological roles and therapeutic potential of CLKs and their heretofore published small-molecule inhibitors, with a focus on the compounds’ potential to be utilized as quality chemical biology probes. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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15 pages, 1845 KiB

Open AccessReview

HSP90 Inhibition and Modulation of the Proteome: Therapeutical Implications for Idiopathic Pulmonary Fibrosis (IPF)

by Ruben Manuel Luciano Colunga Biancatelli, Pavel Solopov, Betsy Gregory and John D. Catravas

Int. J. Mol. Sci. 2020, 21(15), 5286; https://doi.org/10.3390/ijms21155286 - 25 Jul 2020

Cited by 34 | Viewed by 6062

Abstract

Idiopathic Pulmonary fibrosis (IPF) is a catastrophic disease with poor outcomes and limited pharmacological approaches. Heat shock protein 90 (HSP90) has been recently involved in the wound-healing pathological response that leads to collagen deposition in patients with IPF and its inhibition represents an exciting drug target against the development of pulmonary fibrosis. Under physiological conditions, HSP90 guarantees proteostasis through the refolding of damaged proteins and the degradation of irreversibly damaged ones. Additionally, its inhibition, by specific HSP90 inhibitors (e.g., 17 AAG, 17 DAG, and AUY-922) has proven beneficial in different preclinical models of human disease. HSP90 inhibition modulates a complex subset of kinases and interferes with intracellular signaling pathways and proteome regulation. In this review, we evaluated the current evidence and rationale for the use of HSP90 inhibitors in the treatment of pulmonary fibrosis, discussed the intracellular pathways involved, described the limitations of the current understanding and provided insights for future research. Full article

(This article belongs to the Special Issue Targeting the Untargeted Proteome: From Structure-Based Inhibitor Discovery to Chemical Biology and Beyond)

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